Population studies have shown that low-density lipoprotein cholesterol (LDL-C) is directly and high-density lipoprotein cholesterol (HDL-C) is inversely associated with the risk of coronary heart disease (CHD).1-3 While statins and other classes of drugs efficiently reduce LDL-C and concomitantly lower the risk of cardiovascular events,4 evidence for independent atheroprotective effects of HDL-C elevation is inconsistent.5 The anti-atherogenic properties of an HDL particle include the ability to promote transport of cholesterol from peripheral tissues such as the artery wall to the liver as well as anti-inflammatory, anti-apoptotic, nitric oxide-promoting, prostacyclin-stabilizing, and platelet-inhibiting functions.6 However, changes in HDL-C among all trials using hypolipidemic drugs did not independently predict changes in CHD; and the lack of CHD reduction in trials of a novel drug that raises HDL-C by an unprecedented amount suggests that the level of total circulating HDL-C is an insufficient measure of potentially cardioprotective HDL functions.7-9 Metabolic heterogeneity of HDL particles may underlie the inconsistency between epidemiological studies, which consistently show independent risk prediction, and experimental approaches in clinical trials of lipid treatments. HDL comprises a diverse group of lipoproteins with substantial differences in size, density, and composition of lipids and proteins that influences the functional properties and metabolism of the particles.10-12 Thus, it is likely that subpopulations of HDL with more or less anti-atherogenic potential can be identified. Although differential relations with risk of CVD have been observed for various HDL sub-group measures (e.g., particle size, various components, particle concentration, and anti-inflammatory properties), it remains inconclusive whether any of these techniques lead to potential gain in information in terms of CVD risk prediction.13-18 Efforts to identify characteristics that may modulate the functional properties and metabolism of the HDL particle are important to improve the understanding of the atherosclerotic process and to prevent and treat cardiovascular diseases.
Previous work found that apolipoprotein (apo) CIII, a small pro-inflammatory protein that resides on the surface of some lipoproteins,19,20 strongly increased the atherogenicity of VLDL and LDL,21,22 and increased the prediction of risk.23,24 Although HDL particles exist both with and without apoCIII, little is known about the role of apoCIII in relation to HDL function.